The enzyme, aldose reductase (AR), has been implicated in diabetic complications of the nerve, kidney, retina and lens. Currently, a variety of AR inhibitors are being tested as a possible new treatment modality for diabetics, although side effects are always a concern. In order to study the function and expression of AR, we initiated a study on the structure of aldose reductase using peptide and DNA sequencing. We have successfully sequenced over 85% of the aldose reductase protein. Fifteen lambda gt11 rat lens cDNA clones were isolated using oligonucleotide probes designed from partial amino acid sequence of purified rat lens AR. One of the clones gave hybridization with two separate probes and was subsequently sequenced. The insert is 1206 bp in length with an open reading frame encoding 284 amino acids (or a molecular size around 32,300 daltons). The sequences from six rat lens tryptic and cyanogen bromide-cleaved peptide fragments (totally 128 amino acids) are accounted for within the open reading frame of the cDNA insert, indicating that this insert encodes rat lens AR. The sequence of AR has significant similarity (50%) with both human liver aldehyde reductase and frog lens rho crystallin. Local identities as high as 84% were observed. This degree of similarity suggests that all three proteins belong to the same superfamily with related structures and evolutionary origins.